Targeting Langerhans cells via skin delivery of HIV Envelope enhances the antibody response to vaccination

Targeting dendritic cells (DCs) with antigens is a promising approach to modulating T follicular helper (Tfh) cells and germinal center (GC) reactions, enhancing vaccine-induced adaptive immune responses, with preclinical studies highlighting a key role of Langerhans cells (LCs) in generating HIV-1-specific antibody responses. This study evaluated the immunogenicity of a Langerin-targeting vaccine (αLang.Env), comprising an anti-mouse Langerin mAb fused to HIV-1 Envelope 96ZM651 gp140 (Env), delivered through various skin immunization routes in mice, and explored the roles of epidermal LCs and dermal cDC1s in adaptive immune responses. Lymph nodes draining the immunization sites were analyzed using ovalbumin (OVA) as a surrogate antigen after topical (top.), subcutaneous (s.c.), intradermal (i.d.), or transcutaneous (t.c.) delivery via laser-guided microporation, with αLang.Env administered without adjuvant in a Prime-Boost scheme. All methods primed T cells in draining lymph nodes (dLN), as shown by OVA-specific CD8⁺ and CD4⁺ T cell proliferation, while αLang.Env induced GC B cells regardless of the route. However, topical delivery did not elicit Tfh cells or Env-specific GC B cells, whereas i.d. and s.c. routes produced systemic Env-specific IgG responses, with i.d. immunization yielding the highest titers and strongest Tfh responses. In the Xcr1^DTA mouse model, where cDC1s were depleted, the i.d. route confirmed that epidermal LCs were the primary drivers of GC/Tfh reactions and humoral responses, while cDC1s mediated CD8⁺ T cell effector responses. These findings highlight that i.d. administration of the HIV-1 Env antigen targeted to Langerin, without the use of an adjuvant, is an effective vaccine strategy for eliciting GC reactions in LN and generating robust antibody responses, primarily through the activation of LC.